AbbVie’s upadacitinib shows positive results as monotherapy in Phase 3 rheumatoid arthritis study, meeting all primary and key secondary endpoints.
AbbVie, a global research and development-based biopharmaceutical company, announced positive top-line results from the Phase 3 SELECT-MONOTHERAPY clinical trial.
The ongoing study evaluated upadacitinib (ABT-494), an investigational oral JAK1-selective inhibitor, as a monotherapy treatment in patients with moderate to severe rheumatoid arthritis (RA) who did not adequately respond to treatment with methotrexate.
Results showed that after 14 weeks of treatment, both once-daily doses of upadacitinib (15 mg and 30 mg) met the study’s primary endpoints of ACR20** and low disease activity (LDA)*** versus continuing prior stable methotrexate therapy.1 Both doses also achieved all ranked and all key secondary endpoints.1 Upadacitinib is not approved by regulatory authorities and its safety and efficacy have not been established.
“The positive results from the SELECT-MONOTHERAPY study are encouraging, as they are the first evidence to support the potential of upadacitinib as a therapy without the need for background methotrexate,” said Michael Severino, M.D., executive vice president, research and development and chief scientific officer, AbbVie. “These findings add to the growing body of data showing the potential for upadacitinib as a meaningful treatment option for patients suffering from rheumatoid arthritis. We look forward to sharing additional data from the upadacitinib Phase 3 rheumatoid arthritis program with the scientific community in 2018.”
Rheumatoid arthritis, which affects an estimated 23.7 million people worldwide, is a chronic and debilitating disease.14Methotrexate is commonly used as a first-line therapy in rheumatoid arthritis, but many patients do not respond to or cannot tolerate methotrexate, which puts them at risk for disease progression.15-17
“This trial addresses the clinical impact of switching from methotrexate to upadacitinib as monotherapy in patients with an inadequate response to methotrexate. Results suggested that both doses of upadacitinib can provide clinically meaningful responses,” said Josef S. Smolen, M.D., Department of Medicine, Division of Rheumatology, Medical University of Vienna, Austria, and an investigator in the study. “These findings support the potential for upadacitinib monotherapy as a treatment option for patients with rheumatoid arthritis.”
The study showed that at week 14, 68/42/23 percent of patients switched to 15 mg once-daily upadacitinib and 71/52/33 percent of patients switched to 30 mg once-daily upadacitinib achieved an ACR20/50/70** response, compared to 41/15/3 percent of patients continuing on methotrexate.1 These results were statistically significant (p<0.001 for all comparisons) compared to patients who continued on their baseline methotrexate dose.1
Additionally, a significantly higher proportion of upadacitinib patients in both dose groups achieved LDA and clinical remission targets at week 14 compared to patients continuing on methotrexate (p<0.001).1 Low disease activity was achieved by 45 percent and 53 percent of patients in the 15 mg and 30 mg groups, respectively, compared to 19 percent of patients continuing on methotrexate.1 Clinical remission was achieved by 28 percent and 41 percent of patients in the 15 mg and 30 mg groups, respectively, compared to 8 percent of patients continuing on methotrexate.1
SELECT-MONOTHERAPY Efficacy Results at Week 14* |
|||
Methotrexate (n=216) |
Upadacitinib 15 mg (n=217) |
Upadacitinib 30 mg (n=215) |
|
ACR20** |
41% |
68% |
71% |
ACR50** |
15% |
42% |
52% |
ACR70** |
3% |
23% |
33% |
LDA*** |
19% |
45% |
53% |
Clinical Remission**** |
8% |
28% |
41% |
*All week 14 endpoints shown in the table achieved p-values of <0.001 versus methotrexate for both doses. Not all ranked secondary endpoints shown. ACR50 and ACR70 were not ranked secondary endpoints. Methotrexate patients shown are patients who continued on their baseline methotrexate dose in a blinded manner. |
**ACR20/50/70 is defined as American College of Rheumatology 20 percent/50 percent/70 percent improvements in both tender and swollen joint counts, plus 3 of the following: patient assessments of pain, global disease activity and physical function, physician global assessment of disease activity and acute phase reactant. |
*** LDA was defined by a clinical response Disease Activity Score with 28 joint counts (C-reactive protein) (DAS28 [CRP]) less than or equal to 3.2. |
**** Clinical remission was based on DAS28 (CRP) less than 2.6. |
In this study, the safety profile of upadacitinib was consistent with previously reported Phase 3 SELECT clinical trials and Phase 2 studies.1-5 No new safety signals were detected.1 Serious adverse events occurred in 5/3 percent of patients in the 15 mg/30 mg upadacitinib groups, respectively, compared to 3 percent in the methotrexate group.1
One patient, with pre-existing cardiovascular risk factors, had a fatal event of hemorrhagic stroke caused by a ruptured aneurysm, while receiving upadacitinib 15 mg.1 There was one event of pulmonary embolism (PE) in the study, which occurred in the 15 mg dose group in a patient with pre-existing risk factors for PE.1 Across the SELECT rheumatoid arthritis program, including both the placebo-controlled and extension periods, the rate of deep vein thrombosis and PE remains consistent with the background rate for the RA patient population.1-3,18,19
Further results of SELECT-MONOTHERAPY, the third of six studies in the SELECT rheumatoid arthritis clinical trial program, will be presented at a future medical meeting and published in a peer-reviewed publication.
AbbVie is evaluating the potential of upadacitinib across several immune-mediated conditions. Phase 3 trials in psoriatic arthritis are ongoing, and it is also being investigated to treat Crohn’s disease, ulcerative colitis, ankylosing spondylitis and atopic dermatitis.8-13
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References:
1 AbbVie. Data on File, ABVRRTI65458.
2 AbbVie. Data on File, ABVRRTI64730.
3 AbbVie. Data on File, ABVRRTI64466.
4 Kremer JM, Emery P, Camp HS, et al. A Phase 2b study of ABT-494, a selective JAK1 inhibitor, in patients with rheumatoid arthritis and an inadequate response to anti-TNF therapy. Arthritis Rheumatol 2016; (doi:10.1002/art.39801):July 7 [Epub ahead of print].
5 Genovese MC, Smolen JS, Weinblatt ME, et al. A randomized Phase 2b study of ABT-494, a selective JAK1 inhibitor in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Rheumatol 2016;(doi: 10.1002/art.39808):July 7 [Epub ahead of print].
6 Voss, J, et al; Pharmacodynamics Of a Novel Jak1 Selective Inhibitor In Rat Arthritis and Anemia Models and In Healthy Human Subjects. [abstract]. Arthritis Rheum 2013;65 Suppl 10 :2374. DOI: 10.1002/art.2013.65.issue-s10
7 Pipeline – Our Science | AbbVie. AbbVie. 2017. Available at: https://www.abbvie.com/our-science/pipeline.html. Accessed December 19, 2017.
8 A Study Comparing ABT-494 to Placebo in Subjects With Rheumatoid Arthritis on a Stable Dose of Conventional Synthetic Disease-Modifying Antirheumatic Drugs (csDMARDs) Who Have an Inadequate Response to csDMARDs Alone (SELECT-NEXT) – Full Text View – ClinicalTrials.gov. Clinicaltrialsgov. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02675426?term=select+next&rank=1. Accessed December 19, 2017.
9 A Study Comparing ABT-494 to Placebo and to Adalimumab in Participants With Psoriatic Arthritis Who Have an Inadequate Response to at Least One Non-Biologic Disease Modifying Anti-Rheumatic Drug (SELECT – PsA 1). Clinicaltrialsgov. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT03104400?term=ABT-494&phase=2&rank=10. Accessed December 19, 2017.
10 A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of ABT-494 for the Induction of Symptomatic and Endoscopic Remission in Subjects With Moderately to Severely Active Crohn’s Disease Who Have Inadequately Responded to or Are Intolerant to Immunomodulators or Anti-TNF Therapy – Full Text View – ClinicalTrials.gov. Clinicaltrialsgov. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02365649. Accessed December 19, 2017.
11 A Study to Evaluate the Safety and Efficacy of ABT-494 for Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis. Clinicaltrialsgov. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02819635. Accessed December 19, 2017.
12 A Study Evaluating the Safety and Efficacy of Upadacitinib in Subjects With Active Ankylosing Spondylitis (SELECT Axis 1). 2017. Available at: https://clinicaltrials.gov/ct2/show/study/NCT03178487?term=ABT-494&cond=ankylosing+spondylitis&rank=1. Accessed December 19, 2017.
13 A Study to Evaluate ABT-494 in Adult Subjects With Moderate to Severe Atopic Dermatitis. Clinicaltrialsgov. 2017. Available at: https://clinicaltrials.gov/ct2/show/NCT02925117. Accessed December 19, 2017.
14 World Health Organization. The Global Burden of Disease, 2004 Update. Available at: https://www.who.int/healthinfo/global_burden_disease/GBD_report_2004update_full.pdf. Accessed December 19, 2017.
15 Shinde, CG, Venkatesh, MP, Pramod Kumar, TM, Shivakumar, HG. J Pain Palliat Care Pharmacother. 2014 Dec;28(4):351-8. doi: 10.3109/15360288.2014.959238. Epub 2014 Oct 16.
16 Swierkot J and Szechinski J. Methotrexate in rheumatoid arthritis. Pharmacol Rep. 20116 Jul-Aug;58(4)473-92.
17 Fautrel B, Nab HW, et al. Identifying patients with rheumatoid arthritis with moderate disease activity at risk of significant radiographic progression despite methotrexate treatment. RMD Open. 2015; 1(1). DOI: 10.1136/rmdopen-2014-000018.
18 AbbVie. Data on File, ABVRRTI64959.
19 Kim SC. Risk of Venous Thromboembolism in Patients with Rheumatoid Arthritis. Arthritis Care & Research. Vol. 65, No. 10, October 2013, pp 1600–1607.
(Source: AbbVie)
Filed Under: Drug Discovery